Introduction
Methods
Results and discussion
Epidemiology and prognosis of HF in T2DM
Pathophysiology of HF in T2DM
Characteristics of HF in T2DM
HFrEF vs HFpEF in T2DM
Study | SOLVD treatment | MERIT-HF | CIBIS-II | COPERNICUS | EMPHASIS |
---|---|---|---|---|---|
Year completed | 1991 | 1999 | 1999 | 2001 | 2011 |
Number of participants Mean age (years) | 2569 60.8 | 3991 63.8 | 2647 61 | 2289 63.3 | 2737 68.7 |
Duration of follow-up | Mean 41.4 months | Mean 1 year | 1.3 yrs | Mean 10.4 months | Median 21 months |
Drug studied | Enalapril vs placebo | Metoprolol CR/XL vs placebo | Bisoprolol vs placebo | Carvedilol vs placebo | Eplerenone vs placebo |
Inclusion criteria/ EF criterion for entry | Congestive HF with EF ≤ 35% | HF NYHA class II-IV and EF ≤ 40% | HF NYHA class III-IV and EF ≤ 35% | Severe chronic HF with EF < 25% | HF NYHA class II and EF ≤ 35% |
Background HF treatment | Diuretics: 85% β-blockers: 8% Digitalis: 67% Vasodilators: 67% | Diuretics: 91% ACEi/ARBs: 96% Digitoxin: 64% | Diuretics: 99% ACE i: 96% Dihydropyridine Ca antagonists: 2% Nitrates: 58% Digoxin: 52% | Diuretics: 99% ACE i/ARBs: 97% Spironoloactone: 20% Digitalis: 66% | Diuretics: 84% β -blockers: 87% ACEi/ARBs or both: 93% Digitalis: 27% |
Participants with diabetes n (%) | 26% | 984 (25%) | 12% | 26% | 859 (31%) |
Results in the overall population | |||||
Primary endpoint | All-cause death: RR 16% (95% CI 5.26), p < 0.0036 | All-cause death: HR 0.66 (0.53, 0.81), p = 0.00009 | All-cause death: HR 0.66 (0.54, 0.81), p < 0.0001 | All-cause death: RR 35% (18, 48%), p = 0.00013 | CV death or hospitalization for HF: HR 0.63 (0.54, 0.74), p < 0.001 |
Secondary endpoints | All-cause death or hospitalization for HF: RR 26% (95% CI 18, 34), p < 0.0001 | CV death: HR 0.62 (0.50, 0.78), p = 0.0003 All-cause death or hospitalization for HF: RR 31% (20%, 40%), p < 0.001 Hospitalization for HF: 10% (met) vs 14.7% (pbo), p < 0.001 | CV death: HR 0.71 (0.56–0.90) p = 0.0049 Exploratory endpoint: hospitalization for HF. HR 0.64 (0.53–0.79) p < 0.0001 | Death or hospitalization for any reason: RR 24% (13, 33%), p < 0.001 | CV death: HR 0.76 (0.47, 0.70), p = 0.01 Hospitalization for HF: HR 0.58 (0.47, 0.70), p < 0.001 |
Results in the diabetes subpopulation | |||||
Primary endpoint | All-cause death: Non-significant p for interaction | All-cause death: HR 0.82 (0.56, 1.19), p > 0.2 | All-cause death: HR 0.81 (0.51, 1.28) | All-cause death: RR 35% (16, 50%) | CV death or hospitalization for HF: HR 0.541 (0.418, 0.699), p < 0.0001. p for interaction: 0.10 |
Secondary endpoint | All-cause death or hospitalization for HF Non-significant p for interaction | HF hospitalization: RR 37% (53%, 15%; p = 0 .0026 | NR | NR | NR |
References |
Study | DIG trial | Val-HeFt | CHARM overall study program | SHIFT | PARADIGM-HF |
---|---|---|---|---|---|
Year completed | 1997 | 2001 | 2003 | 2010 | 2014 |
Number of participants Mean age (yrs) | 6800 63.5 | 5010 62.7 | 7599 66.0 | 6505 60.4 | 8399 63.8 |
Duration of follow-up | Mean 37 months | Mean 23 months | Median 37.7 months | Median 22.9 months | Median 27 months |
Drug studied | Digoxin vs placebo | Valsartan vs placebo | Candesartan vs placebo | Ivabradine vs placebo | LCZ696 vs enalapril |
Inclusion criteria/ EF criterion for entry | HF with EF ≤ 45% and sinus rhythm | HF NYHA class II-IV and EF < 40% | EF > 40%➔Preserved EF ≤ 40% with ACE inhibitor➔Added EF ≤ 40% with ACE inhibitor intolerance➔ Alternative | Chronic HF with EF ≤ 35% and sinus rhythm with heart rate ≥ 70beats per minute | HF NYHA class II-IV and EF ≤ 40% |
Background HF treatment | Diuretics: 82% ACEi: 94% Nitrates: 43% Other vasodilators: 1% | Diuretics: 85% β -blockers: 35% ACEi: 93% Spironolactone: 5% Digoxin: 67% | Diuretics: 83% β-blockers: 55% ACEi: 41% Spironolactone: 17% Ca antagonists: 20% Digoxin/digitalis glycosides: 43% Other vasodilators: 38% | Diuretics: 83% β-blockers:89% ACEi: 78% ARBs:14% Aldosterone antagonists: 60% Cardiac glycosides: 22% | Diuretics: 80% β-blockers: 93% Mineralocorticoid antagonists: 55% Digitalis: 30% |
Participants with diabetes n (%) | 1933 (28%) | 25% | 2160 (28%) | 1979 (30%) | 2907 (35%) |
Results in the overall population | |||||
Primary endpoint | All-cause death: HR 0.99 (0.91, 1.07), p = 0.80 | All-cause death: HR 1.02 (0.88, 1.18), p = 0.80 Mortality and morbidity*: HR 0.87 (0.77, 0.97), p = 0.009 | All-cause death: HR 0.91 (0.83, 1.00), p = 0.055 | CV death or hospitalization for HF: HR 0.82 (0.75, 0.90), p < 0.0001 | CV death or hospitalization for HF: HR 0.80 (0.73, 0.87), p < 0.001 |
Secondary endpoints | CV death: HR 1.01 (0.93, 1.10), p = 0.78 Hospitalization for HF: HR 0.72 (0.66, 0.79), p < 0.001 CV death or hospitalization for HF: HR 0.85 (0.79, 0.91), p < 0.001 | Hospitalization for HF: RR 27.5%, p < 0.001 | CV death or unplanned admission for HF:HR 0.84 (0.77, 0.91), p < 0.0001 CV death: HR 0.88 (0.79, 0.97), p = 0.012 | All-cause death: HR 0.90 (0.80, 1.02), p = 0.092 Hospitalization for HF: HR 0.74 (0.66, 0.83), p < 0.0001 | CV death: HR 0.80 (0.71, 0.89), p < 0.001 Hospitalization for HF: HR 0.79 (0.71, 0.89), p < 0.001 |
Results in the diabetes subpopulation | |||||
Primary endpoint | All-cause death: HR 1.04 (0.91, 1.20), p = 0.40 | Mortality and morbidity*: non-significant interaction | NR | CV death or hospitalization for HF: HR 0.81 (0.69, 0.95), p for interaction 0.861 | CV death or hospitalization for HF: HR 0.87 (0.77, 0.98), p for interaction: 0.40 |
Secondary endpoint | CV death: HR 1.06 (0.92, 1.24), p for interaction: 0.47 Hospitalization for HF: HR 0.79 (0.68, 0.91), p for interaction: 0.14 CV death or hospitalization for HF: HR 0.90 (0.80, 1.01), p for interaction: 0.27 | NR | CV death or unplanned admission for HF: p for interaction 0.09 | Hospitalization for HF: 0.71 (0.59, 0.86), p = 0.001 | Hospitalization for HF: HR 0.79 (0.67, 0.94) |
References | [75] | [22] | [24] | [27] |
Interventions addressing HF outcomes in patients with T2DM
Non-glycemic interventions
HFpEF—some considerations
Renin-angiotensin-aldosterone system inhibition
Beta (β) blockers
Diuretics
Digoxin
Angiotensin receptor-neprilysin inhibitor
Ivabradine
Glycemic interventions
PROactive | EXAMINE | SAVOR-TIMI 53 | TECOS | ELIXA | LEADER | EMPA-REG OUTCOME | CANVAS | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Key incl. crit | Established CV disease | Acute coronary syndrome within 15–90 days | Established CV disease or high CV risk | Established CV disease or high CV risk | Acute coronary syndrome within 180 days | Established CV disease or high CV risk | Established CV disease | Established CV disease or high CV risk | ||||||||
Key excl. crit | NYHA II-IV | NYHA IV | Se-Creat > 6 mg/dL | eGFR < 30 ml/min/1.732 | eGFR < 30 ml/min/1.732 | NYHA IV | eGFR < 30 ml/min/1.732 | eGFR≤ 30 ml/min/1.732 | ||||||||
Pio | Pbo | Alo | Pbo | Saxa | Pbo | Sita | Pbo | Lixi | Pbo | Lira | Pbo | Empa | Pbo | Ca | Pbo | |
Mean | ||||||||||||||||
age (yrs) | 61.9 | 61.6 | 61.0 | 61.0 | 65.1 | 65.0 | 65.4 | 65.5 | 59.9 | 60.6 | 64.2 | 64.4 | 63.1 | 63.2 | na | 63.4 |
T2D Duration* (yrs) | 8 | 8 | 7.1 | 7.3 | 10.3 | 10.3 | 11.6 | 11.6 | 9.2 | 9.4 | 12.8 | 12.9 | 57.4% | 57.0% | 63.2 | 13.7 |
HbA1c, % | 7.8 | 7.9 | 8.0 | 8.0 | 8.0 | 8.0 | 7.2 | 7.2 | 7.7 | 7.6 | 8.7 | 8.7 | 8.1 | 8.1 | 13.5 | 8.2 |
Trial duration# | 34.5 months | 18 months | 2.1 yrs | 3.0 yrs | 25 months | 3.8 yrs | 3.1 yrs | 126.1 weeks | ||||||||
n
| 5238 | 5380 | 16,492 | 14,671 | 6068 | 9340 | 7020 | 10,142 | ||||||||
Rand. | 1:1 | 1:1 | 1:1 | 1:1 | 1:1 | 1:1 | 2:1 | 2:1, 1:1¤ | ||||||||
Dosages studied | Pio 15.30 or 45 mg | Alo 6.25, 12.5 or 25 mg | Saxa 2.5 or 5 mg | Sita 50 or 100 mg | Lixi 10 or 20 μg | Lira 0.6, 1.2 or 1.8 mg | Empa 10 or 25 mg | Cana 100 or 300 mg | ||||||||
Treatment effects on HF hospitalization in overall group | ||||||||||||||||
Pio | Pbo | Alo | Pbo | Saxa | Pbo | Sita | Pbo | Lixi | Pbo | Lira | Pbo | Empa | Pbo | Cana | Pbo | |
N
| 2605 | 2633 | 2701 | 2679 | 8210 | 8212 | 7332 | 7339 | 3034 | 3034 | 4668 | 4672 | 4687 | 2333 | 5795 | 4347 |
% (n) HFH | 5.7% (149) | 4.1% (108) | 3.9% (106) | 3.3% (89) | 3.5% (289) | 2.8% (228) | 3.1% (228) | 3.1% (229) | 4.0% (122) | 4.2% (127) | 4.7% (218) | 5.3% (248) | 2.7% (126) | 4.1% (95) | 2.1% (123) | 2.8% (120) |
HR (95% CI) HFH | 1.41 (1.10, 1.80), p = 0.007 | 1.19 (0.9, 1.58) p = 0.220 | 1.27 (1.07, 1.51) p = 0.007 | 1.00 (0.83, 1.19) p = 0.95 | 0.96 (0.75, 1.23) p = 0.75 | 0.87 (0.73, 1.05) p = 0.14 | 0.65 (0.50, 0.85) p = 0.0017 | 0.67 (0.52–0.87) | ||||||||
Treatment effects on HF hospitalization in subgroup without prevalent HF | ||||||||||||||||
% (n) without prevalent HF | 100% (2605) | 100% (2633) | 71.5% (1930) | 71.6% (1917) | 87.2% (7154) | 87.2% (7163) | 82.2% (6029) | 81.7% (5999) | 77.5% (2352) | 77.7% (2358) | 86.0% (4015) | 86.0% (4020) | 90.1% (4225) | 89.5% (2089) | 86.1% (4992) | 84.9% (3689) |
% (n) HFH | 5.7% (149) | 4.1% (108) | 2.2% (42) | 1.3% (23) | 2.3% (165) | 1.7% (126) | 2.2% (131) | 2.3% (135) | 2.4% (56) | 2.5% (58) | 3.3% (131) | 3.9% (90) | 1.8% (78) | 3.1% (65) | Not reported | |
HR (95% CI) HFH | 1.41 (1.10, 1.80) | 1.76 (1.07, 2.90) | 1.32 (1.04, 1.66) | 0.96 (0.76, 1.23) | 0.89 (0.67, 1.40) | 0.82 (0.65, 1.04) | 0.59 (0.43, 0.82) | Not reported | ||||||||
Treatment effects on HF hospitalization in subgroup with prevalent HF | ||||||||||||||||
% (n) with prevalent HF | N/A | N/A | 28.5% (771) | 28.4% (762) | 12.8% (1056) | 12.8% (1049) | 17.8% (1303) | 18.3% (1340) | 22.5% (682) | 22.3% (676) | 14.0% (653) | 14.0% (652) | 9.9% (462) | 10.5% (244) | 13.9% (803) | 15.1% (658) |
% (n) HFH | N/A | N//A | 8.2% (63) | 8.5% (65) | 11.7% (124) | 10.2% (102) | 7.4% (97) | 7.0% (94) | 9.7% (66) | 10.2% (69) | 13.3% (87) | 13.8% (90) | 10.4% (48) | 12.3% (30) | Not reported | |
HR (95%CI) HFH | N/A | 1.00 (0.71, 1.42) p = 0.996 | 1.21 (0.99, 1.58) p = 0.15 | 1.03 (0.77, 1.36) | 0.93 (0.66, 1.30) | 0.95 (0.71, 1.28) | 0.75 (0,48, 1.19) | Not reported | ||||||||
Reference | [105] | |||||||||||||||
Abbreviations | *“median duration” given in PROactive and “% with > 10 years duration” given in EMPA-REG OUTCOME #: mean given in PROactive, all others are median ¤: CANVAS was 2:1 randomization, whereas CANVAS-R was 1:1 yrs – years, T2D – type 2 diabetes, cv – cardiovascular, HFH – heart failure hospitalization, Rand- randomization |